Thienylalkyl esters



Patented Feb. 13, 1951 UNITED STAT ES Q'FFI'CE 2,541,024 THIENYLALKYTJ EsTEits Frederick ii ieke, Ann Arbor, Mieh essredr w Reg eats er The University of Michigan, Arbor, Michl, a corporation of Michigan No Drawing. Application September 9; I946; Serial No. 695,811

This invention relates to certain basic-alkyl esters of substituted (alpha-thienyDaliphatic acids, the salts of such esters, and pharmaceutical productsinwhich they are employed as active ingredients. This application is a continuation-inpart of my prior-filed copending h application Serial 575,929, filed February 2, l945,= which has been abandoned.

One of the principal objects of the present invention is the provision of a series of, compounds having utility as pharmaceuticals and particularly as antispasmodic agents. Members of this new group of compounds have been prepared, identified and found to have value as antispasniodicsand as the active ingredients in antispasmodic preparations for the relief of muscle spasm as determined by the method of Magnus (Archiv. den gesammte Physiologic, 1905, vol. 108, pages 1-71). The free basic esters of this group of compounds are usually oily liquids with rela-- wherein R represents hydrogen or a hydrocarbon radical, m represents zero or a positive integer from 1 to 5, inclusive, the carbon chain is straight or branched and contains from 1 to 8" carbon atoms, inclusive, X is hydrogen or a hydroity radical, and Z is a primary or secondary amine radicals Within the meaning ofR in the above formula I- include such hydrocarbon radicals as alkyl radicals, for example, methyl, isopropyl and noctyl; aryl radicals, such as phenyl, naphthyl and para-xenyl; cycloalkyl radicals, such as cyclohexyl; cycloalkylalkyl radicals, such as cyclohegiylethyl andcyclohexylmethyl; aralkyl radicals, such as phenethyl, phenmethyl; alkaryl radicals, such as ethylphenyl; alkylcycloalkyl radicalssuch as ethylcycloh'exyl; alkylcycloalkylalkyl radicals, such as methylcyclohexylethyl; and alkylar'alk'yl radicals, such as ethylphenmethyl. Such hydrocarbon radicals preferably 14" Claims; (01. 260--329) 2. contain not more than: twelve carbon atoms-,regardless of the structure of the substituent.

The primary and secondary amine radicals represented by Z include" such radicals as monomethylamino, monoethylamino, mo'nopropylamino, i'sopropylamino; monobutylamino,n-octylamino; monocyclohexylami-no, diethylamino, di isopropylamino, dibutylamino, dicyclohexylamino, diphenylamino, phenylethylamino, and the like;

The compounds: included within the scope of the present invention include (co) compounds of the above general formula and (b) salts thereof.

The term salts includes acid salts, such as'the citrate, tartrate, hydrochloride, hydrobromide, hydrosulfate, and many others, as well as the quaternary ammonium salts, such as the methobromide, ethochloride and ethyl paratoluenesulfonate. The acid salts may be prepared from the free basic ester by treatment with the selected acid, while the quaternary ammonium salts are prepared by treatment of the free basic ester with the desired alkyl halide or aryl sulfonic ester. When the ester is formed by a reaction of an acid and an alkyl halide, or by the reaction of an acid halide and an alcohol, the ester usually precipitates as the hydrohalide salt.

The hydrocarbon-substituted thienylaliphatic ac'ids' employed as starting materials may be prepared by first reacting thiophene with an acid halide of a monoester of oxalic acid, e. g., ethyl oizalyl chloride, ClCO-COOC2H5, in the presence of aluminum chloride, to produce an alkyl ester of an alpha-thienyl keto acid, such as ethyl (alpha-thienyl) glyoxylate,

The keto'acidl obtained by' hydrolysisoftlie ester, is then reacted with Grig'I-iard reagent containing the selected hydrocarbon radical and the resulting complex is decomposed with a suitable acidic reagent, such as 1101, NH4C1, Nazism, et ceter'a, to produce a substituted thienyl' by"- dr'oxyaliphatic'" acid having" a hydrocarbon radical attached to a carbon atom" of the aliphatic chain; This compound may be employedwithout further modification in the production of the hydroxycontaining basic ester, or it may be reduced, e. g., with stannous chloride, to produce the corre= sponding hyaro'xwrree hydrocarbon-substituted thienylaliphatic acid and thereafter treated to prepare the basic ester.

As an alternative procedure, the acyl halide of the alkyl monoester of oxalic acid may first be reacted with a suitable hydrocarbon such as benzene, biphenyl(para-xenyl radical) naphthalene, et cetera, in the presence of aluminum chloride, to produce the corresponding substituted keto acid, the latter hydrolysed to the free acid, and the acid then reacted with a Grignard reagent containing a thienyl radical. Decomposition of the magnesium-containing complex with acid and reduction .of the hydroxy acid may be carried out as described in the preceding paragraph. I

The preparations and examples herein will serve to illustrate procedure whereby production of members of this newgroup of compounds may be accomplished, butrare in'no way to be construed as limiting. a

PREPARATION 1.--ETHYL (ALPHA- THIENYL) GLYOXYLATE A mixture of 84 grams (l'mole) of thiophene, 137 grams (1 mole) of ethyl oxalyl chloride and 1500milliliters of tetrachloroethane was cooled to minus 5 degrees centigrade and 147 grams (1.1

moles) of aluminum chloride was added portiona 'was then dried with anhydrous sodium sulfate,

and fractionally distilled. A yield of 93 grams of ethyl (alpha-thienyl) glyoxylate, boiling at 115- 120 degrees centigrade at three millimeters of mercury pressure absolute, was obtained.

PREPARATION 3.-SUBSTITUTED HYDROXY ACIDS A solution of methyl magnesium iodide (prepared by reacting 85.2 grams (0.6 mole) of methyl iodide with 14.4 grams (0.6 mole) of magnesium in 300 milliliters of diethyl ether) was added dropwise and with stirring to 31.2 grams (0.2 mole) of (alpha-thienyl)glyoxylic acid dissolved in 300 milliliters of ether and cooled with a mix ture of ice and salt. An immediate vigorous reaction occurred and a precipitate separated. The mixture was stirred for one hour at room temperature, heated to boiling under reflux for two hours, cooled, and the ether layer decanted and discarded. The granular residue was washed with ether, decomposed with dilute sulfuric acid, extracted with ether, and the ether extract washed with an excess of aqueous twenty per cent sodium carbonate solution. The alkaline wash liquor was clarified with activated carbon, filtered, and the filtrate acidified with dilute sulfuric acid. The precipitate was separated. washed with ether, and dried. After recrystallisation from benzene there was obtained grams of methyl-(alpha-thienyl)hydroxyacetic acid melting at 1ll-113 degrees centigrade.

By substituting cyclohexyl, benzyl, phenyl, para-xenyl, alpha-naphthyl, phenethyl, cyclohexylethyl or similar magnesium halides, for the methyl magnesium iodide employed in the preparation just described, the corresponding substitut-d (alpha-thienyl)hydroxyacetic acids are obtained. a

In Table I there are given the melting points, empirical formulae, and analyses of representative hydroxy acids employed in accordance with the present invention.

Table I Sulfur, Per Cent Melting Empirical Point, 0. Formula Calc'd Found Mcthgl-(al pha-thienyDhydmxyacetic 111-113 masons... 18.162; 18.34 801 Cyclohegiyl-(alpha-thicnyl)hydroxyace- 1 125426 CuHitOsS--. 13. 34 13. 30

1c 1101 Ben zdyl-(alpha-thienyhhydroxyacetic 140-152 CnHnOzSm 12. 87 12.97

ac: PlierilyH al p h a thicnybhydroxyacetic 1 3 128- C HflJOgS.-. 13.65 13. 56

am (para-xenyD-(alp ha-thienyDhydroxy- 1 129-130 015 114033-..- 10. 33 10. 28 aceticacid. (alpha-naphthyl)-(alpha-thienyl)- 101-102 C16H1203s 11.27 11.33 hydroxyacetic acid. v '1 1 Reerystalliscd from benzene. 9 Recrystallised from dilute acetic acid.

8 Decomposed.

PREPARATION 2.(ALPHA-THIENYL) GLY ,OXYLIC ACID- A mixture of grams of ethylialpha-thi- PREPARATION 4.--NON-HYDROXY Aonjs In the preparation of thienyl-substituted fatty acids from the hydroxy acids just described the latterare reduced, preferably with stannous chloride. In a representative operation, 12 grains (0.051 mole) of phenyl-(alpha-thienyl)hydroxy: aceticacid, 24 grams (0.106 mole) of stannous chloride dihydrate and 200 milliliters of acetic acid were stirred together. Hydrogen chloride was passed into the mixture with agitation at 15 degrees centigrade. After three hours, the mixextract washed with waterand evaporated to 7c ture was blown with air to remove acetic acid;

vtive the residue mixed with ice-water and filtered.

:The residue, after washing with water and re crystallising from fifty per cent acetic acid, weighed 7 grams and consisted of. phenyl-(alphathienyDaoetic acid.

In Table II there are given the melting points, empirical formulae, and analyses of representahydrocarbon-substituted (alpha thienyl) acetic acids employed as reactants in preparing the compounds of the invention. The compounds were purified by recrystallising from dilute acetic acid.

6. solution was dried and the solvent removed. The desired productwas obtained in 66- per c'ent yield (93 grams) and boiled at 119-121 degrees-centigrade at 23 millimeters of mercury pressure.

PREPARATION 8.-BETA'-(ALPl-IA THIENYL)ETHLY CHLORIDE A solution of (alpha-thienyDmagnesium bro-- mide, prepared from 97.8 grams of alpha broniothiophene; 14.6 grams of magnesium and 3'75 milliliters of ether, was stirred and 280 grams of beta-ehloroethyl (para-toluene)sulfonate, dissolved. in 300 milliliters of ether, was added drop PREPARATION 5.ALPHA-THIENYLMETHYL CHLORIDE A rapid stream of hydrogen chloride-waspassedinto a stirred mixture of 525 milliliters of conc'entr'ated hydrochloric acid, 450 milliliters of 40 per cent aqueous formaldehyde, and 465- milliliters of thiophen'e at a temperature between zero and five degrees centigrade. After saturation with the gas, the material was poured into twolitersof water, the oily precipitate separated, and the aqueous layer extracted several times with ether. Extracts and the oil were combined, washed with water and dried over potassium carbonate. After removalof the ether, the product' boiled at 78-82 degrees centigrade at 18 millimeters of mercury pressure. The yield was 373 grams, or 47 per cent of the theoretical.

The chloride should not be kept in a tightly closed container since it undergoes spontaneous decomposition, often with explosive violence. If preserved in a refrigerator, the compound remains undecomposed for some time.

PREPARATION 6-. (ALPHA-THIENYLJACE- TONITRILE A mixture of 133 grams of (alpha-thienylimethyl chloride, 650 milliliters of acetone, and 74 grams of sodium cyanide dissolved in 100-milliliters of water, stirred and heated in a waterbath at Gil-65 degrees centigrade for fourhours. Water was added, the organic layer separated and added to the ether extract of the aqueous layer. The ether was removed from the dried solution and the nitrile distilled. The nitrile boiled at 115-120 degrees centigrade' at 22 millimeters of mercury pressure. The yield was 100 grams, or 81 per cent of thetheoretical.

PREPARATION 7. (AL1='HA-THIENYL) ACETATE A mixture of 100 grams of (alpha-thienyhacetonitrile, 225 milliliters of 95 per cent alcohol and 7 milliliters of water was poured into a citrate bottle and saturated with hydrogen chloride at a temperature between zero and five degrees Centigrade. After 12 hours at room temperature, the mixture was heated for two hours on a steam-bath, cooled, 150' milliliters of water added, and the oily layer separated and added to the ether extract of the aqueous layer. The

wise thereto. A solid began to precipitate after about one-half of the ester had been added. The mixture was stirred and refluxed for five hours, cooled to between five and ten degrees centigrade, and 100' milliliters of concentrated hydrochloric acid diluted with 350 milliliters of water was added thereto. An amount of water sufficient to dissolve the precipitate was then added and the ether layer was washed with sodium bicarbonate solution and dried with potassium carbonate. The chloride boiled at 88-92 degrees centigrade at 20 millimeters of mercury pressure. The yield was 62.6 grams, or 71.4 per cent of the theoretical. The analysis showed Cell-7801 to contain 24.05 per cent chloride as compared with the theoretical of 24.19.

PREPARATION 9.MONO SUBSTITUTED MALONIC ESTERS For the preparation of diethyl (alpha-thienyl) malonate and diethyl phenylmalonate, the procedure of Wallingford et a1. (Wallingford, Homeyer and Jones, J. Am. Chem. Soc. 63, 2056 (1931) for the latter compound was employed. It-was found that simple apparatus consisting only of a three-neck, 500-rnilliliter flask fitted with inclined condenser and sealed stirrer was satisfactory. Excess diethyl carbonate was used due to unavoidable loss of this substance from the reaction mixture during removal of the alcohol.

To obtain diethyl (alpha-thienyl)malonate, a solution of sodium ethylate, prepared from 18.5 grams of sodium and 300 milliliters of alcohol, was heated in an oil-bath, stirred and the alcohol removed under reduced pressure. The cake or sodium ethylate was broken into small pieces and 650- milliliters of diethyl carbonate, followed by 132.4 grams of ethyl (-alpha-thienyl) -acetate, was added. The mixture was stirred at -85 degrees centigrade and the alcohol was removed, as fast as formed, at 300-320 millimeters of mercury pressure. After five hours the distillate. a mixture of alcohol and diethyl carbonate, amounted to about 200 milliliters. The material was poured into a mixture of water and ice to which 90 milliliters of concentrated hydrochloric acid had been added. The organic layer was separated, combined with the benzene extract of the aqueous layer, and shaken with water, After removai of excess benzene and diethyl carbonate,

answer 7 the'diethyl- (alpha-thienyl)malonate (l-l'r lf ms) boiled at 148-151 degrees centigrade at*6 millimeters of mercury pressure.

Bythe employment of the same procedure, diethyl phenylmalonate was obtained in 83 per cent yield.

Allother monosubstituted malonic' esters were .prepared by the procedure used for diethyl betav(alpha-thienyl)ethylmalonate described below. l

PREPARATION l0.--DIETHYL BETA-(AI.-

PHA-THIENYL) -ETHYLMALONATE A solution of sodium ethylate, prepared from '7 .8 grams of sodium and 135 milliliters of-etha-nol,

.was warmed to 50 degrees centigrade and; 32 grams of diethyl cyclohexylmethylmalonate (8111 Table III hereinafter), was added. After the mixture had refluxed for a few minutes, 24.9 grams of (alpha-thienyDmethyl chloride, was added dropwise at a rate such that the mixture continued to reflux. After about three hours at reflux, the product was isolated in the usual manner.

' The boiling points of some of the thus-prepared monoand disubstituted malonic esters are given in Table III. 5

was warmed to 50 degrees centigrade and 81 .5

grams of diethyl malonate was added thereto. The mixture was heated to the boiling point and 50.5 grams of beta'-(alpha-thienyl) ethyl chloride was added slowly. The mixture was refluxed for twenty hours, alcohol removed under reduced pressure, Water added to the oily residue, and the mixture neutralized with dilute hydrochloric acid. The organic layer was separated and combined with the benzene extract of the aqueous layer. After removal of solvent, the ester boiled at 150-154 degrees centigrade at 4 millimetersof mercury pressure. The yield was 46.7 grams or 51 per cent of the theoretical.

PREPARATION 11.-DIsUBsTI TIJTED MALONIC EsTERs I! Diethyl beta-cyclohexylethyl-(alpha-thienyl) methylmalonate and diethyl cyclohexyl-(alpha- .;thienyl)methylmalonate were obtained by the method described below for the latter ester.

The alcohol was removed under reduced pressure from a solution of sodium ethylate and 2 00 milliliters of diethyl carbonate and 48.4 grams of diethyl c clohexylmalonate was added. The mix- A solution of sodium ethylate, obtained from glas r le lll o m. d. lll l le 9 lc lll (alpha-Thlenyl)methyl chloride was used to prepare all the disubstiluted esters except 3, 4, and-5; benz chloride was employed for 3, beta-phenethyl bromide for 4, and beta-cyclohexylethyl bromide for 5. Each disub stituted ester was obtained from the monosubstituted ester indicated by a corresponding number.

When this compound '(C H3SCH CH(COOC H was hydrolyzed with a mixture of water, alcohol and potassium hydroxide, it yielded (alpha-thienynmetliylmalomc acid; M. P. 138-139 degrees centigrade after ,re crystallisation from an acetone-benzene mixture. Ahab ysis: Calcula ed for (3 11 0 8: S, 16.01. Found: S,

h This substance (U tl3SCH UH(C00C2H was converted by hydrolysis into beta-(2-thienyl)ethyl1nalcnic .acld; P. 130-131 degrees centigrade after recrystallisation from acetone-benzene. Analysis: Calculated for anthems: 8. 14.97. Found: S. 14.90. Uyclohexyl.

The preparation of malonic acids and acetic acids is further illustrated by the following procedure.

PREPARATION 13.-( A L P H A THIENYL'lj METHYL-CYCLOHEXYIMETHYLMALONIC ACID 1 A mixture of 30.5 grams of diethyl (alpha thienyl) -methyl-cyclohexylmethylmalonate, prepared according to the foregoing methods, and 19.6 grams of potassium hydroxide, dissolved in 20 milliliters of water andflfi milliliters of alcohol, was refluxed for twenty hours. The waterand alcohol were then 'removed under reduced pressure, the residue dissolved in a small amount of water, the solution cooled to about five degrees centigrade, 550 milliliters of ether added, andtil? mixture acidified with concentrated hydrochloric acid. The ether layer was separated and mixed with the ether extract of the aqueous layer. After washing the ether solution with water, it

. was dried over magnesium sulfate and the solvent removed to give the desired product in a yield of about per cent.

PREPARATION 14.(ALPHA THIENYD- METHYL CYCLOHEXYLMETHYLACETIC ACID, ET CETERA 59 Some substituted thienylmethylmalonic and :thienylmethylacetic acids thus prepared and physical constants thereof .are'givenzin TableIV.

Table I V may then be dried and volatilizedin accordance with conventional methods.

To produce quaternary ammonium salts, the

SUB BTIHU-TED "(ALPHA-'THIENYL) METHYLMALONIG AND (ALPHA-THIENYL)- .METHYL ACE-TIC ACIDS Oalc'd. Found Cl'cd. Found 1.0m, 12196-197 (5 mm.) .L 73-74 13.50 14509 "2.C H5CHz 1'62 11.05 11;81' 2'.2l22l4 (7111111.) 70*71 "13.112 12.99 aGEmQHZQHZH 1156-157 110. 53 19.30, 3f.'224-226 (3 mm.) o l, 4.'C 'H SCH CH 167-168 20. 65 20. 50 42232-333 (8 mm.) p11 5.G H 5'.l7ll 76 (3mm) (12-63 Tl-3.46 E13. 28 611111 10112 151-152 10. 82 10. 79 62205-206 (6 111111;) 54-56 12. 70 I2. 73 7.05H11CH2CH 126-127 10.33 10.14 7.21l2l2 (5 mm) 011 811-03131 130-131 -13. 23 13. 21 8 .150-162 (6 mm.) 011 I Cyclohexyl.

Malonic acids 1 and 5 lost carbon dioxide spontaneously with the formation of the corresponding acetic acid.

Malonic acid 2 was recrystallised from water, 3 .and .4 from a mixture .of .loenzeneeace'tone, and

6, 7 and 8 from a mixture of petro eum ether.

Acetic acid 2 was recrystallised from a mixture of .benzene and petroleum ether; all other acetic acids from petroleum ether.

In the preparation of the :hydrohalides of the basic-alkyl esters of the hydrocarbon-substituted thienyl aliphatic acids, substantially equimolar proportions'ofa basic-alkyl halide and the hydrocarbon-substituted thienylaliphatic acid are admixed in a suitable solvent, -e. g.,ethano1 or isopropyl alcohol, and the mixture heated until reaction has occurred. This may occur at room temperatureor require heating at reflux for some time, e. g., 4 .to 16 hours, more or less. The crude salt may be crystallised by dissolving it in a small quantity of warmethanol, adding d'iethyl ether until turbidity and thereafter cooling the mixture. The salt separates in crystalline form and is recovered by decantation or filtration. Other acid salts may be obtained in a similar manner from the .free basic ester. As the antispasmodic activity of the esters apparently resides in the ester itself, and not in the saltpor'tion of the molecule, any acid .may be employed without detracting materially from the eifectiveness of the compound, provided only that the anion 0f the acid employed be reasonably non-toxic, and therefore thesalt to beproduced isusually chosen primarily with regard to .crystallinity and solubility.

As an alternative method of salt formation, a non-hydroxy acid may be converted to the acid chloride, as by heating with thionyl chloride, and the acid chloride then reacted with the selected basic alcohol to form the desired ester hydrochloride. The former method is preferred, however, since higher yields of product are obtained thereby.

The free basic-alkyl esters may be obtained from the hydrohalides bytreatment with aqueous sodium carbonate or other .mild alkali, preferably at low temperatures, and thereafter extracting with ether .or other suitable solvent. The solvent several times.

free base may be warmed with alkyl halides, such as methyl bromide, ethyl chloride, propyl iodide, et cetera, or with the selected aryl sulfonic ester such as ethyl para-toluene-sulfonate, under which conditions the corresponding quaternary salt is usually formed in high yields.

EXAMPLE 1. 3 DIETHYLAMINOPROPYL PHENYL (ALPHA THIENYL) HYDROXY ACETATE HYDROCHLORIDE A mixture of 3.4 grams of phenyl-(alphathienyl) hydroxy acetic acid, 2.2 grams of 3-diiethy'laminopropyl chloride and 50 milliliters of 'isopropyl alcohol was refluxed for twelve hours.

After milliliters of absolute alcohol had been added to the cold mixture, it was treated with Norite activated carbon at room temperature, filtered, and the Norite treatment repeated The solvents were removed from the filtrate under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride (4.6 grams) was recrystallised from a mixture of absolute alcohol and absolute ether; melting point, 142-145 degrees centigrade.

EXAMPLE 2. 3 DIETHYLAMINOPROPYL PHENYL- (ALPHA-THIENYL) ACETATE HY- DROCHLORIDE A mixture of 2.7 grams (0.0125 mole) of phen- 'yl-(alpha-thienyl) acetic acid, 1.7 grams ,0.0l25

mole) of 3-diethylaminopropyl chloride and 50 milliliters of isopropyl alcohol was refluxed for twelve hours. The cold solution was mixed with .150 milliliters of absolute alcohol, shaken with Norite ;at ordinary temperature, filtered, the liltratetreated again with Norite, and the mixture filtered. The solvents were removed under reduced pressure, and the residue rubbed under absolute ether. The crude ester hydrochloride ("2.5 grams) was recrystallised several times from benzene; melting point 87-89 degrees centigrade.

E XAM P L E 3. 2 DIETHYLAMINOETHYL (PARA XENYL) (ALPHA TI-IIENYL) ACE- TATE HYDROCHLORIDE A mixture of 4.4 grams (0.015 mole) of (paraxenyl)(alpha-thienylacetic acid and 5.5 milliliters of pure thionyl chloride was refluxed for one and one-half hours in an oil bath. After t e addition of 10 milliliters of ,dry benzene to r 11 thedark browri mixture which contained the acid chloride, the benzene and excess thionyl chloride were removed under reduced pressure. Another 10 milliliters of benzene was added, re-

12 EXAMPLE 5.--2-DIETHYLAMINOETHYL P H N Y L (ALPHA -"'I HIE HYDROCHLORIDE A mixture of 4.36 grams of phenyl-(alpha-thimoved by distillation, and this process repeated 5 several times. The residue was cooled and disenyl) acetic acid, 2.75 grams of 2-diethylaminozolverlhin 5 milligegs 01f bi g g 11 3 3%- ethyl chloride and 40"mi'1-1iliters--of isopropyl aliOn ere Was a e 1 0w Y grams 0 cohol was refluxed for 15 hours. Isopropyl alethylaminoethanol: and themixturewas reflux-ed cohol "was removed under reduced --pressure,- the 5:3 3:23 gggg i g igf fii 3253 residue dissolved in absolute alcohohidecolorized cous mass was d ssolved in 201) milliliters 01 abfiltergd and'alcohol removedlbywdlsr solute alcohol and the solution treated with The resldue wa rubbed f. absolute Norite several times. The solvent was removed g f if l fg f r g g g g began 3 hyunder diminished pressure, and the..11ght gre l T: 1 a 25?? 9 is ish-yellow, oily ester hydrochloride was rubbed n T b V are F {neltmg P9 1 1 under absolute ether until it became crystalline. in some cases; 9 1 5 P 2 v 0 5011 3 1??? It was recrystallised from a mixture of absolute and S t therdof h h 11 e n e f-t qalcohol and absolute ether; me1ting=-p'oint..101. p nt Invention 11 1 103 degrees centigrade. V bl' EXAMPLE 4.2DIETHYLAMINOETHYL 1 PHENYL (ALPHA J'THIENYL) HYDROXY'-'" ACETATE HYDROCHLORIDE .rPhenyl (alpha -;thienyl)hydroxyacetic acid y 0 4)m Jo001111101 (4.86 grams), Z-diethylaminoethyl chloride (2.85 X

m x R R1 /M.P.,C

1 O H OH2CH2N(C2H5)2 99-101 2 0 H 1n 115-117 3 0 H do 0541s 1 4 0 H dn 197-199 0.2 mm.) 5 0 H do 181-183 e 0 do 141-142 7 0 CH2CH9CH2N(C2H5)2 87-89 3 0 do 102-105 001111111.

9 0 :1n 142-143 10 O -CH2CH2CH2N(C4H9)2 131-133 11 0 dr- 155-150 12 0 CH2CH N(isoCaH1)2 99-100 13 0 5n 1 174-176 (0.05 mm.) q 14 '0 do 156-157 15 0 -CHzCHzN(CHa)9 113-115 16 0 d0 156-160 (0.01 mm.) 9 17 0 159-116 1 1s 0 dn '189.5-191 19 0 CH2CH2N(C4H9)2 180-183 (0.01 mm.) '20 0 do 119-120 21 0 -CH2C(CH1)2CHzN(CHs)2 126-128 1 22 0 .....55 142-144 23 o -CH(CH5)CH2N(C2H5)2....- 102-105 (0.01 mm) 24 0, 55 141-142 25 0 CH1CH2NHCH9 139-140 26 0 -OH2CH2NH(C5H5) 154-155 27 0 CH2CH2N(C2H5)(Cfi 5)--- 160-162" 28 0 --CHzCH2N(CaHu)2 184-185 29 0 dn 175-175 80 0 CH2CH2NH(C5H11) 151-152 31 0 do 194-195 32 1 CH2CH4N(C2H5)2 -1 94-95 33 0 CH2CH2CH2N(C2H3) 134-136 34 1 CH2CHzN(C2H5)2 119-120 35 1 C 2OH2NHC 130-131 36 1. CHzCH2N(C2H5)z 97-98 37 0 CH2GH2CH2N(C2H5)2 152-154 38 1 H -CH2CH2N(C2H5)2 152-154 39 0 dn aboveZOO 40 1 H camera dn 89-91 41 1 H omnomomnundo 103-105 42 1 H n-om (In 113-114 43 0 .OH om rln 119-121 44 0 OH alpha-010111--- do -1. 203 45 0' H d -CH2CH2CH2N(C4H0) 162-164 5 45 0 .H CH2CH1CH2N(02H-) 151-153 g g C2CH2 zH5)2 'hydrobromide. methobromide. free base,B.P.,C. xenyl. decomposed.

grams) and 75 milliliters'of isopropyl alcohol were "refluxed for 15-hours.- After-the addition 015;; milliliters of absolute alcohol to the cold mixture, it was treated with Norite-(activ ted charcoal) at room temperature, filtered, and the v solvents removed under" reduced pressure; The residue crystallised when 'triturated with absolute ether.' After recrystallisation from absolute alcohol, the hydrochloride melted 5 5-131-182 deg'reescentigrade. 1

.Still another procedure which may be employed for the production of some of the esters involves the preparation of the desired acid halide, such' as (alpha-thienyl)methyl-benzylacetyl chloride:

(B. P., -175" C. at 5 mm.), preparation of an amide, e. g., N-methyl-N-(beta'-hydroxyethyl)- (alpha-thienyl) methyl-benzylacetamide (B; P.,

-190 C. at 0.05 mm., M. P., 55-57 C.), by re- 75 aminoalkanol in an aqueous alkaline medium,

NYLldCETATE V cyclohexyl. "paraand conversion of the amide into the ester according to the directions of Reasonberg and Goldberg, J. Am. Chem. Soc. 67, 933 (1945) Z-methylaminoethyl (alpha-thienyl)methyl-benzylacetate hydrochloride, prepared in this manner, melts at 130-131 degrees centigrade.

Other compounds Within the scope of the present invention include 2-butylaminoethy1 (alphathienyl)acetate hydrochloride, 3-amylaminopropyl (alpha-thienyDacetate hydrobromide, 2-ethylamino (alpha-thienyl)butylacetate ethochloride, 4-ethylaminobutyl (alpha-thienyDpropylacetate ethyl (para-toluene)sulfonate, 2-dipropylaminoethyl (alpha-thienyl)pro-pyl-phenethylacetate hydrobromide, 5-diethylaminoamyl (alpha-thienyl) butyl-ethylcyclohexylacetate hydrosulfate, 2-ethylaminoethyl (alpha-thienyl)methyl-ethylphenylacetate hydrochloride, 2-cycl0- hexylethylaminoethyl (alpha thienyl) -methylphenethylacetate hydrochloride, 2-dimethylaminoethyl (alpha-thienyD methyl-ethylcyclohexylethylacetate hydrochloride, Z-diethylaminoethyl (alpha-thienyDacetate hydrochloride, 2-diethylaminoethyl (alpha-thienyl) ethyl-hydroxyacetate hydrochloride, and the like, all of which may be prepared according to the foregoing disclosure.

The preferred embodiment of the present invention resides in compounds of the formula wherein m, X, the carbon chain, and Z have the values previously given, and wherein R is hydrogen or a hydrocarbon radical selected from the group consisting of alkyl, aryl, cycloalkyl, aralkyl and cyoloalkylalkyl, which compounds have exhibited exceptional antispasmodic activity. Some of the compounds also exhibt local anesthetic and mydriatic eifects.

Attention is directed to my application Serial No. 125,380, filed November 3, 1949, in which is claimed subject matter disclosed but not claimed herein.

It is to be understood that many variations may be made without departing from the spirit and scope of the invention, and that I am to be limited only by the appended claims.

I claim:

1. A compound selected from the group consisting of (a) basic-alkyl esters of the formula I (Z-thienyl) 0 Hz) m|CC 0 0 carbon chainZ wherein R represents a hydrocarbon radical, m represents a number from 0 to 5, inclusive, the carbon chain is straight or branched and contains from 1 to 8 carbon atoms, inclusive, X is selected from the group consisting of hydrogen and hydroxy radicals, and Z is selected from the group consisting of primary and secondary amine radicals, and (b) salts thereof.

2. A compound selected from the group consisting of (a) basic-alkyl esters of the formula R (2-thienyl)(CH,) r-G 0 O-carb on chain-Z wherein R represents a carbocyclic hydrocarbon radical, m represents a number from 1 to 5, inclusive, the carbon chain is straight or branched and contains from 1 to 8 carbon atoms, inclusive, X is selected from the group consisting of hydrogen and hydroxy radicals, and Z is selected from the group consisting of primary and secondary amine radicals,and (b) salts thereof.

3. A salt of a compound having the formula R (2-thienyl) (011;) m ll-C O 0carbon chain-2;

wherein R represents a six-carbon-atom carbocyclic hydrocarbon radical, m represents a number from 1 to 5, inclusive, the carbon chain is straight or branched and contains from 1 to 8 carbon atoms, inclusive, X is selected from the group consisting of hydrogen and, hydroxy radicals, and Z is selected from the group consisting of primary and secondary amine radicals.

4. A compound as defined in claim 3, wherein R is the phenyl radical.

5. A compound as defined in claim 3, wherein R is thecyclohexyl radical.

6. A compound as defined in claim 1, in which Z is a lower dialkylamino radical, and m represents the number 1.

'7. A compound as defined in claim 3, in which R is a lower alkyl radical.

8. A compound as defined in claim 3, in which R is a benzyl radical.

9. A compound as defined in claim 3, in which R is a cyclohexylmethyl radical.

10. 2 -diethylamin0ethyl cyclohexyl- (alphathienyl) methylacetate hydrochloride.

11. Z-dithylaminoethyl phenyl (alpha-thienyl) methylacetate hydrobromide.

12. 2-diethylaminoethyl n-propyl-(alpha-thienyl) methylacetate hydrochloride.

13. 2 .diethylaminoethyl benzyl (alpha-thienyl) methylacetate hydrochloride.

14. 2-diethylaminoethy1 cyclohexylmethyl-(alpha-thienyl) methylacetate hydrochloride.

FREDERICK F. BLICKE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,367,702 Van Zoeren Jan. 23, 1945 OTHER REFERENCES 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) BASIC-ALKYL ESTERS OF THE FORMULA 